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ANTIMALARIAL DRUGS PowerPoint Presentation
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  2. ANTIMALARIAL DRUGS ILOs By the end of this lecture you will be able to: Classify the main antimalarial drugs depending on their target of action Detail the pharmacokinetics & dynamics of main drugs used to treat attack or prevent relapses Compare the mechanism and major ADRs of adjunctive drugs used in combinations State the WHO therapeutic strategy for treatment

  3. What are the Targets of Treating an infected patient? N.B.If patient has got infected by sporozoites we want to protect against progression to Tissue Shizontocides  Primaquine

  4. TREAT ATTACK • LACTONE ENDOPEROXIDES ARTEMISININ ARTENUSATE ARTEMETHER ARTEMISININ Poor solubility Soluble • Fast acting blood Schizontocide Affect all forms including multi-drug resistant P. falciparum Pharmacokinetics Derivatives are rapidly absorbed orally Rapidly biotransform in liver into artenimol active metabolite Widely distributed t½ artemisinin 4hrs/ artesunate  45min / artemether 4-11hrs Artemesiaannua Mechanism They have endoperoxide bridges that are cleaved by haemiorn to yeild carbon-centred free radicals, that will Alkylate membranes of parasite’s food vacuole and mitochondria no energy Irreversibly bind & inhibit sarco-endoplasmic reticulum Ca2+-ATPase of the parasite, thereby inhibiting its growth Inhibiting formation of transport vesicles no food vacuoles

  5. TREAT ATTACK • LACTONE ENDOPEROXIDES ARTEMISININ ARTENUSATE ARTEMETHER ARTEMISININ ADRs Transient heart block neutrophil count Brief episodes of fever Neuro, hepatoand bone marrow toxicity Resistance was reported recently in Cambodia- Thailand border

  6. TREAT ATTACK • LACTONE ENDOPEROXIDES ARTEMISININ ARTENUSATE ARTEMETHER ARTEMISININ Preparations Artesunate IV or IM preparations for severe complicated cases as cerebral malaria (24h) followed by complete course of ACT • Artemisin-based combination therapies (ACTs): • Artemether + lumefantrine • Artemether + amodiaquine • Artemether + mefloquine • Artemether + sulfadoxine-pyrimethamine Artemisinin and its derivatives should not be used as monotherapy.(Recrudescence)

  7. TREAT ATTACK 4-AMINOQUINOLINES Chloroquine and Amodiaquine CHLOROQUINE • Potent blood Schizontocide & Gametoside Can be active against all forms of the schizonts (exception is chloroquine-resistant P.f. & P.v.) Against P.v., P.o., P.m Pharmacokinetics • Rapidly & completely absorbed from the GIT • Has high volume of distribution(100-1000l/kg) • Concentrated into parasitized RBCs. • Released slowly from tissues • Metabolized in the liver • Excreted in the urine 70% unchanged • Initial t½ =2-3days & terminal t ½=1-2months • Chloroquine concentrates  1000-fold in food vacuole of parasite. Why ??? • Its protonation & ion trapping due to  pH of vacuole • Its active uptake by a parasite transporter(s) • Its binding to a specific receptor in the food vacuole.

  8. TREAT ATTACK 4-AMINOQUINOLINES CHLOROQUINE Mechanism Malaria Parasite digest host cell’s Hbto obtain a.a. Heme is released  Toxic So parasite detoxifies it by heme polymerase Hemozin(NonToxic) & traps it in food vacuole RBC Food vacuole Malaria Parasite (Hz) (Hb) (Heme) (Heme) (Hemozin) (Hb) X Heme Polymerase X CHLOROQUINE Peptides CHLOROQUINE concentrate inside acidic food vacuole Lysis N.B. It is used also in rheumatoid arthritis, SLE,….

  9. TREAT ATTACK 4-AMINOQUINOLINES CHLOROQUINE ADRs Short-term 1. Mild headache and visual disturbances 2. Gastro-intestinal upsets; Nausea, vomiting 3. Pruritus, urticaria. Prolonged therapy Retinopathy, characterized by loss of central visual acuity, macular pigmentation and retinal artery constriction. Progressive visual loss is halted by stopping the drug, but is not reversible??? N.B. Chloroquine concentrates in melanin containing tissues, e.g. the retina. 2. Lichenoidskin eruption, bleaching of hair 4. Weight loss Bolus injection hypotension & dysrrhythmias N.B. Safe in pregnancy

  10. TREAT ATTACK 4-AMINOQUINOLINES CHLOROQUINE Resistance against the drug develops as a result of enhanced efflux of parasite vesicle expression of the human multi drug resistance transporter P-glycoprotein Chloroquine entery EffluxedChloroquine Chloroquine Therapeutic Use:- Used to eradicate blood schizonts of Plasmodium vivax Plasmodium vivaxresistance evolved in Indonesia, Peru and Oceania

  11. TREAT ATTACK AMINOQUINOLINES DERIVATIVE ARYLAMINOALCCOHOLS Quinolinemethanols; quinine, quinidine & mefloquine QUININE Phenanthrenemethanols; halofantrine • Is a the main alkaloid in cinchona bark • Potent blood Schizontocide & weak Gametoside (not P.f) Pharmacokinetics • Rapidly & completely absorbed from the GIT • Peaks after 1-3 hrs • Metabolized in the liver • 5% excreted in the urine unchanged • t½ = 10 hrs but longer in sever falciparum infection • N.B. Administered: orally in a 7 day course • or by slow IV for severe P. falciparum infection Mechanism •  As ANTIMALARIAL  Same as chloroquine Other Actions Quinidine – like action Mild oxytoxic effect on pregnant uterus Slight neuromuscular blocking action Weak antipyretic action

  12. TREAT ATTACK AMINOQUINOLINES DERIVATIVE Resistence like chloroquine by efflux through p-glycoprotein MDR transporter QUININE ADRs • With therapeutic dose  poor compliance  bitter taste. • Higher doses  • Cinchonism(tinnitus, deafness, headaches, nausea & visual disturbances) • Abdominal pain & diarrhea • Rashes, fever, hypersensitivity reactions • Hypotension & arrhythmias • Blood dyscarasis; anaemia, thrombocytopenic purpura& • hypoprothrombinaemia • Blackwater fever, a fatal condition in which acute haemolyticanaemia is associated with renal failure • IV  neurotoxicity  tremor of the lips and limbs, delirium, fits, stimulation followed by depression of respiration & coma N.B. Safe in pregnancy

  13. TREAT ATTACK AMINOQUINOLINES DERIVATIVE QUININE Contraindications Prolonged QT Interval Glucose-6-Phosphate Dehydrogenase Deficiency Myasthenia Gravis Hypersensitivity Optic Neuritis, auditory problems Dose should be reduced in renal insufficiency Interactions Antacids: Antacids containing aluminum &/or magnesium may delay or decrease absorption of quinine. Erythromycin (CYP3A4 inhibitor): Cimetidine Mefloquine. Quinine can raise plasma levels of warfarin and digoxin.

  14. PREVENT RELAPSES 8-AMINOQUINOLINES PRIMAQUINE • Hypnozoitocides against liver hypnozoites & gametocytocides Radical cure of P. ovale & P. vivax Prevent spread of all forms Pharmacokinetics Well absorbed orally Rapidly metabolized to etaquine & tafenoquine more active t½  3-6h Mechanism Not well understood. It may be acting by; Generating ROS  can damage lipids, proteins & nucleic acids Interfering with the electron transport in the parasite  no energy Inhibiting formation of transport vesicles no food vacuoles Resistance;  Rare when primaquine & chloroquine combine

  15. PREVENT RELAPSES 8-AMINOQUINOLINES PRIMAQUINE ADRs At regular doses  patients with G-6-PD deficiency  hemolytic anemia. In G-6-PD deficiency  NADPH, GSH synthesis. So RBCs become sensitive to oxidative agents  HEMOLYSIS Primaquine  Oxidizes GSH to GSSG   GSH   detoxification of toxic products At larger doses  Epigastric distress & abdominal cramps. Mild anemia, cyanosis & methemoglobinemia Severe methemoglobinemia rarely in patients with deficiency of NADH methemoglobinreductase. Granulocytopenia & agranulocytosis rare

  16. WHO TREATMENT GUIDELINES ACT / 3 days followed by Primaquine for 14 days IN VIVAX Resistance Sensitive Chloroquine for 3 days followed by Primaquine for 14 days IN FALCIPARUM All show Resistance Uncomplicated ACT Complicated IV Artisunate for 24 hrs Followed by; ACT Or Artemether+ [Clindamycin / doxycyline] Or Quinine + [Clindamycin / doxycyline]

  17. WHO TREATMENT GUIDELINES IN FALCIPARUM All show Resistance Special Risk Groups Pregnancy; 1st trimester Quinine + Clindamycin (7 days) Pregnancy; 2nd & 3rd trimester Lactating women Infants & young children ACT